1-229431540-CG-C

Position:

• chr1-229431540-CG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PP4 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1092delC (p.Tyr364*) variant in ACTA1 is a deletion variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 363-377) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMIDs:16945536, 17187373). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in one homozygous individual with features consistent with nemaline myopathy, including a muscle biopsy with multiple small nemaline rods in most fibers (PM3, PP4 PMID:17187373). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3, PM2_Supporting, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA915940544/MONDO:0100084/169

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 1.42

Genes affected

ACTA1 (HGNC:129): (actin alpha 1, skeletal muscle) The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]

ENSG00000290037 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.1092delC	p.Tyr364fs	frameshift_variant	7/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.1092delC	p.Tyr364fs	frameshift_variant	7/7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.1014delC	p.Tyr338fs	frameshift_variant	7/7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.957delC	p.Tyr319fs	frameshift_variant	6/6			ENSP00000508084.1
ENSG00000290037	ENST00000702606.1	n.176delG		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Alpha-actinopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The c.1092delC (p.Tyr364*) variant in ACTA1 is a deletion variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 363-377) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong; PMIDs:16945536, 17187373). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in one homozygous individual with features consistent with nemaline myopathy, including a muscle biopsy with multiple small nemaline rods in most fibers (PM3, PP4 PMID:17187373). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3, PM2_Supporting, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-229567287;